Background: Disseminated nocardiosis still causes significant morbidity and mortality and is often caused by Nocardia asteroides, N. basiliensis, and N. farcinica and are often treated with trimethoprim–sulfamethoxazole (TMP–SMX). Nocardia otitidiscaviarum (N. otitidiscaviarum) rarely causes disseminated disease and resistance to TMP–SMX is even more rare. Case presentation: A 37-year-old woman with metastatic breast cancer and right ear deafness with recent occupational gardening and manipulating soil, presented to the hospital with first time seizure and multiple skin nodules. Magnetic resonance imaging (MRI) showed ring enhancing lesions, biopsy of the skin and brain lesions grew N. otitidiscaviarum. She was empirically treated with TMP–SMX and Imipenem–Cilastatin, however, almost three weeks into therapy, susceptibility results revealed it to be resistant to both antimicrobials, she was subsequently changed to Amikacin, Linezolid, Moxifloxacin, and Doxycycline but ultimately died. Conclusions: This case report highlights the importance of suspecting a rare Nocardia species in patients at risk with proper occupational exposure, moreover, TMP–SMX resistance should be suspected with lack of clinical response, this may have important implications on clinical practice when facing similar infections.